Radio-opaque polymer biomaterials

ABSTRACT

Iodinated and/or brominated derivatives of aromatic dihydroxy monomers are prepared and polymerized to form radio-opaque polymers. The monomers may also be copolymerized with other dihydroxy monomers. The iodinated and brominated aromatic dihydroxy monomers can be employed as radio-opacifying, biocompatible non-toxic additives for other polymeric biomaterials. Radio-opaque medical implants and drug delivery devices for implantation prepared from the polymers of the present invention are also disclosed.

CROSS REFERENCE TO RELATED APPLICATION

[0001] This application is a continuation of U.S. patent applicationSer. No. 10/288,076 (pending) which was filed on Nov. 5, 2002 with theUnited States Patent and Trademark Office, which application, in turn,is a Divisional of U.S. patent application Ser. No. 09/554,027 filedJul. 3, 2000 which issued as U.S. Pat. No. 6,475,477 on Nov. 5, 2002,and which claims priority benefit under 35 U.S.C. §371 of PCT/US98/23777filed Nov. 6, 1998, which, in turn, claims priority benefit of U.S.Provisional Patent Application No. 60/064,905, filed on Nov. 7, 1997.The disclosures of the aforementioned applications are incorporatedherein by reference.

GOVERNMENT LICENSE RIGHTS

[0002] The U.S. Government has a paid-up license in this invention andthe right in limited circumstances to require the patent owner tolicense others on reasonable terms as required by the terms of GrantNos. GM-39455 and GM-49849 awarded by the National Institutes of Health.

TECHNICAL FIELD

[0003] The present invention relates to radio-opaque biodegradablepolycarbonates and polyarylates and the block copolymers thereof withpoly(alkylene oxides). In particular, the present invention relates topolycarbonates and polyarylates and the poly(alkylene oxide) blockcopolymers thereof that are radio-opaque as a consequence of beinghomopolymers and copolymers of dihydroxy monomers having iodinated orbrominated aromatic rings as part of their structure.

BACKGROUND OF THE INVENTION

[0004] Diphenols are monomeric starting materials for polycarbonates,polyiminocarbonates, polyarylates, polyurethanes, and the like. Commonlyowned U.S. Pat. Nos. 5,099,060 and 5,198,507 disclose amino acid-deriveddiphenol compounds, useful in the polymerization of polycarbonates andpolyiminocarbonates. The resulting polymers are useful as degradablepolymers in general and as tissue-compatible bioerodible materials formedical uses, in particular. The suitability of these polymers for theirend use application is the result of their polymerization from diphenolsderived from the naturally occurring amino acid, L-tyrosine. Thedisclosures of U.S. Pat. Nos. 5,099,060 and 5,198,507 are herebyincorporated by reference. These previously-known polymers are strong,water-insoluble materials that can best be used as structural implants.

[0005] The same monomeric L-tyrosine derived diphenols are also used inthe synthesis of polyarylates as described in commonly owned U.S. Pat.No. 5,216,115 and in the synthesis of poly(alkylene oxide) blockcopolymers with the aforementioned polycarbonates and polyarylates,which is disclosed in commonly owned U.S. Pat. No. 5,658,995. Thedisclosures of U.S. Pat. Nos. 5,216,115 and 5,658,995 are also herebyincorporated by reference.

[0006] Commonly owned International Application No. WO 98/36013discloses dihydroxy monomers prepared from α-, β- and hydroxy acids andderivatives of L-tyrosine that are also useful starting materials in thepolymerization of polycarbonates, polyiminocarbonates, polyarylates, andthe like. The preparation of polycarbonates, polyarylates andpolyiminocarbonates from these monomers is also disclosed. Thedisclosure of International Application No. WO 98/36013 is also herebyincorporated by reference.

[0007] Synthetic, degradable polymers are currently being evaluated asmedical implants in a wide range of applications, such as orthopedicbone fixation devices, drug delivery systems, cardiovascular implants,and scaffolds for the regeneration/engineering of tissue. Such polymers,when used as implants, are non-traceable without invasive procedures. Aradio-opaque polymer would offer the unique advantage of being traceablevia routine X-ray imaging. The fate of such an implant through variousstages of its utility could be followed without requiring invasivesurgery.

[0008] Davy et al., J. Dentist., 10(3). 254-64 (1982), disclosebrominated derivatives of poly(methyl methacrylate) that areradio-opaque. Copolymerization with non-brominated analogs was requiredto obtain the thermomechanical properties required for its desired useas a denture base. Only in a small range of certain percentageconcentrations of the bromo-derivative does the material exhibitacceptable thermomechanical properties. In addition, there is nodisclosure that the materials exhibiting acceptable properties remainbiocompatible following the addition of bromine to the polymerstructure. In contrast to the polymers disclosed in this application,the brominated poly(methyl methacrylates) do not degrade. However,because the bromine atoms are located on the aliphatic ester side chain,upon side chain ester cleavage, the polymer loses its radio-opacity.

[0009] Horak et al, Biomater., 8, 142-5 (1987), disclose thetriiodobenzoic acid ester of poly(2-hydroxyethyl methacrylate) to beuseful as a radio-opaque X-ray imaging marker compound. The iodinecontent was reported to affect the contrast, volume, mechanicalproperties and hydrophobicity of the polymer. A proper balance ofproperties, including radio-contrast and swellability, was achievedthrough optimization of the iodine content. Again, this material doesnot degrade through the main chain and loses radio-opacity upon sidechain ester cleavage because the iodine atoms are located on the esterside chain.

[0010] Cabasso et al., J. Appl. Polym. Sci., 38, 1653-66 (1989),disclose the preparation of a radio-opaque miscible polymer coordinationcomplex of poly(methyl methacrylate) and a uranium salt, uranyl nitrate.The polymer does not degrade through the main chain and thebiocompatibility of the uranyl nitrate complex is not reported, nor hasthe long-term stability of the complex in vivo been established. Cabassoet al., J. Appl. Polym. Sci., 41, 3025-42 (1990), discloses thepreparation of radio-opaque coordination complexes of bismuth bromideand uranyl hexahydrate with polymers prepared from acrylated phosphorylesters containing 1,3-dioxalane moieties derived from polyols such asglycerol, D-mannitol, D-sorbitol, pentaerythritol and dipentaerythritol.The phosphoryl group was selected to provide stronger coordinating sitesfor the bismuth and uranium salts and to impart adhesive propertiestoward hard tissues. Preliminary biocompatibility data indicatedsatisfactory performance, but the polymer does not degrade through themain chain and the long-term stability of the complex in vivo is notreported.

[0011] Jayakrishnan et al., J. Appl. Polym. Sci., 44, 743-8 (1992),discloses radio-opaque polymers of triiodophenyl methacrylate and of theiothalamic ester of 2-hydroxyethyl methacrylate. Polymers of usefulmolecular weight were not obtained, attributable to the presence ofbulky iodine atoms in the monomer side chain. It was possible to obtaincopolymers with non-iodinated analogs in the presence of crosslinkingagents, such that up to 25% of the iodinated monomer could beincorporated. Preliminary biocompatibility data indicated that thepresence of triiodophenyl methacrylate caused blood hemolysis. Inaddition, the materials also do not degrade through the main chain, andin the event of side chain ester cleavage, would lose theirradio-opacity because of the iodine atoms being located in the sidechain.

[0012] Kraft et al., Biomater., 18 31-36 (1997), discloses thepreparation of radio-opaque iodine-containing poly(methylmethacrylates). The monomers were ortho- and para-iodo and2,3,5-triiodobenzoic acid esters of 2-hydroxymethyl methacrylate, andthe para-iodophenol ester of methyl methacrylic acid. The monomers werecopolymerized with one or more non-iodinated analogs and a small amountof crosslinkers to produce polymer hydrogels with varying iodinecontents. It was reported that the hydrogels were well tolerated bysubcutaneous tissues and that the presence of iodine did not severelyalter the swellability of the hydrogel. No tissue necrosis, abscessformation or acute inflammation was observed, although all implants weresurrounded by a fibrous capsule. However, these materials also do notdegrade through the main polymer chain, and upon side chain estercleavage, lose radio-opacity because of the iodine atoms being locatedin the ester side chain.

[0013] Currently, no technology is available to provide radio-opaquepolymers that degrade through the main polymer chain, such as theabove-discussed tyrosine-derived polymers. For their intended use asmedical implants, radio-opaqueness is a valuable property. A need existsfor radio-opaque polymers that degrade through the main polymer chains,such as the tyrosine-derived polymers discussed above.

SUMMARY OF THE INVENTION

[0014] These needs are met by the present invention. It has now beenfound that iodination or bromination of the aromatic rings of dihydroxymonomers renders the resulting polymers radio-opaque. Significantly, theresulting polymers exhibit good mechanical and engineering propertieswhile degrading into relatively non-toxic products after implantation invivo.

[0015] In general, the ability of a species to absorb X-rays is relateddirectly to atomic number and is approximated by the relationship.

m=kI ³ Z ⁴+0.2

[0016] wherein m is the absorption coefficient, 1 is the wavelength ofthe incident X-ray, Z is the atomic number of the absorbing species andk is the proportionality constant. Iodine and bromine atoms, because oftheir high mass, scatter X-rays and impart radio-opaqueness. This ishighly significant and allows clinicians to visualize any implanteddevice prepared from a radio-opaque polymer by simple X-ray imaging

[0017] Thus, iodinated and/or brominated derivatives of dihydroxymonomers may be prepared and polymerized to form radio-opaquepolycarbonates and polyarylates. These monomers may also becopolymerized with poly(alkylene oxides) and other dihydroxy monomers.In addition, the iodinated and brominated dihydroxy monomers can beemployed as radio-opacifying, biocompatible non-toxic additives forother polymeric biomaterials.

[0018] Therefore, according to one aspect of the present invention, adiphenolic radio-opacifying, biocompatible, non-toxic additive forpolymeric biomaterials is provided having the structure of Formula I:

[0019] Formula I represents a diphenol compound substituted with atleast one bromine or iodine atom, wherein each X₁ and X₂ isindependently an iodine or bromine atom, Y1 and Y2 are independentlybetween zero and two, inclusive, and R₉ is an alkyl, aryl or alkylarylgroup with up to 18 carbon atoms. Preferably, R₉ contains as part of itsstructure a carboxylic acid group or a carboxylic acid ester group,wherein the ester is selected from straight and branched alkyl andalkylaryl groups containing up to 18 carbon atoms in addition to therest of the R₉ structure, and ester derivatives of biologically andpharmaceutically active compounds covalently bonded to the diphenol,which are also not included among the carbons of R₉. R₉ can also containnon-carbon atoms such as iodine, bromine, nitrogen and oxygen.

[0020] In particular, R₉ can have a structure related to derivatives ofthe natural amino acid tyrosine, cinnamic acid, or 3-(4-hydroxyphenyl)propionic acid. In these cases, R₉ assumes the specific structure shownin Formula II:

[0021] R₀ is selected from (—CH═CH—), (—CHJ₁—CHJ₂—) and (—CH₂—)_(d) andR₄ is selected from (—CH=CH—), (—CHJ₁—CHJ₂—) and (—CH₂—)_(a), in which aand d are independently 0 to 8, inclusive, and J₁ and J₂ areindependently Br or I. Z is H, a free carboxylic acid group, or an esteror amide thereof Z preferably is a pendent group having a structureaccording to Formula IV:

[0022] wherein L is selected from hydrogen and straight and branchedalkyl and alkylaryl groups containing up to 18 carbon atoms andderivatives of biologically and pharmaceutically active compoundscovalently bonded to the dihydroxy compound.

[0023] Z can also be a pendent group having a structure according toFormula IVa:

[0024] wherein M is selected from —OH, —NH—NH₂, —O—R₁₀—NH₂, —O—R₁₀—OH,—NH—R₁₀—NH₂, —NH—R₁₀—OH,

[0025] a C-terminus protecting group and a derivative of a biologicallyor pharmaceutically active compound covalently bonded to the pendentfunctional group by means of amide bond, wherein in the underivatizedbiologically of pharmaceutically active compound a primary or secondaryamine is present in the position of the amide bond in the derivative.

[0026] Z can also be a pendent group having a structure represented byFormula IVb:

[0027] wherein M is a derivative of a biologically or pharmaceuticallyactive compound covalently bonded to the pendent functional group bymeans of R₃, wherein R₃ is a linkage selected from —NH—NH— in the casewhen in the underivatized biologically or pharmaceutically activecompound an aldehyde or ketone is present at the position links to thependent functional groups by means of R₃; and —NH—NH—, —NH—R₁₀—NH—,—O—R₁₀—NH—, —O—R₁₀—O— or —NH—R₁₀—O— in the case when in theunderivatized biologically or pharmaceutically active compound acarboxylic acid is present in the position linked to the pendentfunctional group by means of R₃; and

[0028] in the case when in the underivatized biologically orpharmaceutically active compound a primary or secondary amine or primaryhydroxyl is present in the position linked to the pendent functionalgroup by means of R₃.

[0029] R₁₀ is selected from alkyl groups containing from 2 to 6 carbonatoms, aromatic groups, α-, β-, γ- and ω amino acids and peptidesequences.

[0030] According to another aspect of the present invention, aradio-opacifying, biocompatible, non-toxic dihydroxy additive forpolymeric biomaterials is provided having the structure of Formula III:

[0031] Formula III represents a dihydroxy compound substituted with atleast one bromine or iodine atom and having a structure related toderivatives of tyrosine joined by way of an amide linkage to an α-, β-or γ-hydroxy acid or derivative thereof Each X₂ is independently aniodine or bromine atom; Y2 is 1 or 2; R₅ and R₆ are each independentlyselected from H, bromine, iodine and straight and branched alkyl groupshaving up to 18 carbon atoms; R₀ is (—CH₂—)_(d), —CH═CH— or(—CHJ₁—CHJ₂—) and R₁₅ is (—CH₂—)_(m), —CH═CH— or (—CHJ₁—CHJ₂—), whereinJ₁ and J₂ are independently Br or I and d and m are independentlybetween 0 and 8, inclusive. Z is the same as described above withrespect to Formula II.

[0032] According to another aspect of the present invention,radio-opaque biocompatible polymers are provided having monomericrepeating units defined in Formulae Ia and IIIa:

[0033] Formula Ia represents a diphenolic unit wherein X₁, X₂, Y1, Y2and R₉ are the same as described above with respect to Formula I.Formula IIIa represents an aromatic dihydroxy unit wherein X₂, Y2, R₀,R₅, R₆, R₁₅ and Z are the same as described above with respect toFormula III.

[0034] Copolymers in accordance with the present invention have a seconddihydroxy unit defined in Formulae Ib or IIIb.

[0035] In the diphenolic subunit of Formula Ib, R₁₂ is an alkyl, aryl oralkylaryl groupwithupto 18 carbon atoms, preferably substituted with apendent free carboxylic acid group or an ester or amide thereof, whereinthe ester or amide is selected from straight and branched alkyl andalkylaryl esters containing up to 18 carbon atoms, in addition to therest of the R₁₂ structure, and derivatives of biologically andpharmaceutically active compounds covalently bonded to the polymer,which are also not included among the carbons of R₁₂. R₁₂ can alsocontain non-carbon atoms such as nitrogen and oxygen. In particular, R₁₂can have a structure related to derivatives of the natural amino acidtyrosine, cinnamic acid, or 3′(4′-hydroxyphenyl) propionic acid.

[0036] For derivatives of tyrosine, 3′(4′-hydroxyphenyl) propionic acidand cinnamic acid, R₁₂ assumes the specific structure shown in FormulaII in which R₀ is —CH=CH— or (—CH₂—)_(d) and R₄ is —CH═CH— or(—CH₂—)_(a), in which a and d are independently 0 to 8, inclusive. Z isthe same as described above with respect to Formula II.

[0037] In the dihydroxy subunit of Formula IIIb, R₁₆ and R₁₇ are eachindependently selected from H or straight or branched alkyl groupshaving up to 18 carbon atoms; R₁₈ is —CH═CH— or (—CH₂—)_(d) and R₁₉ is—CH═CH— or (—CH₂—)_(e), in which d and e are independently between 0 and8, inclusive. Z is again the same as described above with respect toFormula II.

[0038] Some polymers of this invention may also contain blocks ofpoly(alkylene oxide) as defined in Formula VII. In Formula VII, R₇ isindependently an alkylene group containing up to 4 carbon atoms and k isbetween about 5 and about 3,000.

—(O—R₇)_(k)—O—  (VII)

[0039] A linking bond, designated as “A” is defined to be either

[0040] wherein R₈ is selected from saturated and unsaturated,substituted and unsubstituted alky, aryl and alkylaryl groups containingup to 18 carbon atoms. Thus, polymers in accordance with the presentinvention have the structure of Formulae VIII and VIIIa:

[0041] In both formulae, f and g are the molar ratios of the varioussubunits. The range of f and g can be from 0 to 0.99. It is understoodthat the presentation of both formulae is schematic and that the polymerstructures represented are true random copolymers where the differentsubunits can occur in any random sequence throughout the polymerbackbone. Formulae VIII and VIIIa provide a general chemical descriptionof polycarbonates when A is

[0042] Formulae VIII and VIIIa provide a general description ofpolyarylates when A is

[0043] Furthermore, several limiting cases can be discerned: When g=0,the polymer contains only iodine or bromine-substituted monomericrepeating units. If g is any fraction greater than 0 but smaller than 1,a copolymer is obtained that contains a defined ratio of monomericrepeating units substituted with bromine or iodine and monomericrepeating units that are bromine- and iodine-free.

[0044] If f=0, the polymer will not contain any poly(alkylene oxide)blocks. The frequency at which poly(alkylene oxide) blocks can be foundwithin the polymer backbone increases as the value of f increases.

[0045] The radio-opaque bromine- and iodine-substituted dihydroxycompounds of the present invention meet the need for biocompatiblebiodegradable additives that are miscible with radio-opaque polymericbiomaterials and enhance the radio-opacity of the polymeric materialsTherefore, the present invention also includes the radio-opaque bromine-and iodine-substituted dihydroxy compounds of the present invention,physically admixed, embedded in or dispersed in a biocompatiblebiodegradable polymer matrix. Preferably, the dihydroxy compound is ananalogue of a monomeric repeating unit of the matrix polymer.

[0046] The bromine- and iodine-containing polymers of the presentinvention also meet the need for radio-opaque processible biocompatiblebiodegradable polymers, the radio-opacity of which is not affected byanything other than degradation of the main polymer chain. Therefore,the present invention also includes implantable medical devicescontaining the radio-opaque polymers of the present invention. Theradio-opaque polymers of the present invention thus find application inareas where both structural solid materials and water-soluble materialsare commonly employed.

[0047] Polymers in accordance with the present invention may be preparedhaving good film-forming properties An important phenomena observed forthe polymers of the present invention having poly(alkylene oxide)segments is the temperature dependent face transition of the polymer gelor the polymer solution in aqueous solvents. As the temperatureincreases, the gel of the polymers undergo a face transition to acollapsed state, while polymer solutions precipitate at a certaintemperature or within certain temperature ranges. The polymers of thepresent invention having poly(alkylene oxide) segments, and especiallythose that undergo a phase transition at about 30° to 40° C. on heatingcan be used as biomaterials for drug release and clinical implantationmaterials. Specific applications include films and sheets for theprevention of adhesion and tissue reconstruction.

[0048] Therefore, in another embodiment of the present invention,radio-opaque poly(alkylene oxide) block copolymers of polycarbonates andpolyarylates may be formed into a sheet or a coating for application toexposed injured tissues for use as barrier for the prevention ofsurgical adhesions as described by Urry et al., Mat. Res. Soc. Symp.Proc., 292, 253-64 (1993). Placement of the radio-opaque polymer sheetsof the present invention may be followed by X-ray imaging withoutinvasive surgery. This is particularly useful with endoscopic surgery.Therefore, another aspect of the present invention provides a method forpreventing the formation of adhesions between injured tissues byinserting as a barrier between the injured tissues a sheet or a coatingof the radio-opaque poly(alkylene oxide) block copolymers ofpolycarbonates and polyarylates of the present invention.

[0049] The poly(alkylene oxide) segments decrease the surface adhesionof the polymers of the present invention. As the value of f in FormulaeVIII and VIIIa increases, the surface adhesion decreases. Polymercoating containing poly(alkylene oxide) segments according to thepresent invention may thus be prepared that are resistant to cellattachment and useful non-thrombogenic coatings on surfaces in contactwith blood. Such polymers also resist bacterial adhesion in this, and inother medical applications as well. The present invention thereforeincludes blood contacting devices and medical implants having surfacescoated with the polymers of Formulae VIII and VIIIa in which f isgreater than 0. The surfaces are preferably polymeric surfaces. Methodsaccording to the present invention include implanting in the body of thepatient a blood-contacting device or medical implant having a surfacecoated with the above-described polymers of the present inventioncontaining poly(alkylene oxide) segments.

[0050] Blood contacting or implantable medical devices formed from thepolymers of the present invention are also included in the scope of thepresent invention as well. Such polymers may or may not havepoly(alkylene oxide) segments.

[0051] The present invention also includes microspheres of theradio-opaque polymers of the present invention, useful as X-ray contrastagents or as drug delivery systems, the location of which can be tracedby X-ray imaging. For purposes of the present invention, the term “X-rayimaging” is defined as including essentially any imaging techniqueemploying X-rays, including the extensively practiced procedures ofradiography, photography and Computerized Axial Tomography Scans (CATscans). Methods in accordance with the present invention for thepreparation of drug delivery systems can also be employed in thepreparation of radio-opaque microspheres for drug delivery.

[0052] In another embodiment of the present invention, the polymers arecombined with a quantity of a biologically or pharmaceutically activecompound sufficient for effective site-specific or systemic drugdelivery as described by Gutowska et al., J. Biomater. Res., 29, 811-21(1995), and Hoffman, J. Controlled Release, 6, 297-305 (1987). Thebiologically or pharmaceutically active compound may be physicallyadmixed, embedded in or dispersed in the polymer matrix as if it werenot a radio-opaque polymer, eliminating the need for radio-opaque fillermaterials, thereby increasing the drug loading capacity of the matrixpolymer.

[0053] Another aspect of the present invention provides a method forsite-specific or systemic drug delivery by implanting in the body of apatient in need thereof an implantable drug delivery device containing atherapeutically effective amount of a biologically or pharmaceuticallyactive compound in combination with a radio-opaque polymer of thepresent invention. As noted above, derivatives of biologically andpharmaceutically active compounds can be attached to the polymerbackbone by covalent bonds, which provides for the sustained release ofthe biologically or pharmaceutically active compound by means ofhydrolysis of the covalent bond with the polymer backbone.

[0054] By varying the value of f in the polymers of Formulae VIII andVIIIa, the hydrophilic/hydrophobic ratios of the polymers of the presentinvention can be attenuated to adjust the ability of the polymercoatings to modify cellular behavior. Increasing levels of poly(alkyleneoxide) inhibits cellular attachment, migration and proliferation,increasing the amount of pendent free carboxylic acid group promotescellular attachment, migration and proliferation. Therefore, accordingto yet another aspect of the present invention, a method is provided forregulating cellular attachment, migration and proliferation bycontacting living cells, tissues, or biological fluids containing livingcells with the polymers of the present invention.

[0055] A more complete appreciation of the invention and many otherintended advantages can be readily obtained by reference to thefollowing detailed description of the preferred embodiment and claims,which disclose the principles of the invention and the best modes whichare presently contemplated for carrying them out.

BEST MODES OF CARRYING OUT THE INVENTION

[0056]FIG. 1 is an X-ray image of a radio-opaque polymer pin accordingto the present invention implanted into a section of a rabbit femur.

BEST MODES OF CARRYING OUT THE INVENTION

[0057] The present invention provides radio-opaque polycarbonates andpolyarylates, as well as poly(alkylene oxide) block copolymers thereof,in which the radio-opacity is derived from bromine- andiodine-substitution of some or all of the aromatic rings in the polymerbackbone. The bromine- and iodine-substituted polymers are prepared bybrominating or iodinating a pre-monomer compound prior to synthesis ofthe dihydroxy monomer. The dihydroxy monomer is subsequently polymerizedby established procedures, alone, or in combination with dihydrokycompounds that are not bromine- or iodine-substituted.

[0058] In particular, the bromine- and iodine-substituted dihydroxycompounds include diphenols having the structure of Formula I wherein R₉is the same as described above with respect to Formula I. The diphenolspreferably have the structure of Formula II. Among the preferreddiphenols are compounds in which R₉ has the structure of Formula II inwhich R₄ is —CH₂— or —CHJ₁—CHJ₂—and R₀ is —CH₂— or —CH₂—CH₂—. Mostpreferably, R₄ is —CHJ₁—CHJ₂— and R₀ is —CH₂—. These most preferredcompounds are bromine- and iodine-substituted tyrosine dipeptideanalogues known as desaminotyrosyl-tyrosine, and the alkyl and alkylarylesters thereof. In this preferred group, the diphenols can be regardedas derivatives of tyrosyl-tyrosine dipeptides from which the N-terminalamino group has been removed.

[0059] Diphenol compounds that are not bromine- or iodine-substitutedhave the structure of Formula Ic:

[0060] wherein R₁₂ is the same as described above with respect toFormula Ib. R₁₂ preferably has the structure shown in Formula II inwhich R₀ is —CH═CH— or (—CH₂—)_(d) and R₄ is —CH═CH— or (—CH₂—)_(a), inwhich a and d are independently 0 to 8.

[0061] Methods for preparing the diphenol monomers in which R₉ or R₁₂contain as part of their structures a carboxylic acid ester group aredisclosed in commonly owned U.S. Pat. Nos. 5,587,507 and 5,670,602, thedisclosures of both of which are hereby incorporated by reference. Thepreferred desaminotyrosyl-tyrosine esters are the ethyl, butyl, hexyl,octyl and benzyl esters. For purposes of the present invention,desaminotyrosyl-tyrosine ethyl ester is referred to as DTE,desaminotyrosyl-tyrosine benzyl ester is referred to as DTBn, and thelike. For purposes of the present invention, the non-esterdesaminotyrosyl-tyrosine free carboxylic acid is referred to as DT.

[0062] It is not possible to polymerize the polycarbonates, polyarylatesthe poly(alkylene oxide) block copolymers thereof, having pendent freecarboxylic acid groups from corresponding diphenols with pendent freecarboxylic acid groups without cross-reaction of the free carboxylicacid group with the co-monomer. Accordingly, polycarbonates,polyarylates and the poly(alkylene oxide) block copolymers thereof thatare homopolymers or copolymers of benzylester diphenol monomers such asDTBn may be converted to corresponding free carboxylic acid homopolymersand copolymers through the selective removal of the benzyl groups by thepalladium catalyzed hydrogenolysis method disclosed by co-pending andcommonly owned U.S. patent application Ser. No. 09/056,050, filed onApr. 7, 1998. The disclosure of this application is incorporated hereinby reference. The catalytic hydrogenolysis is necessary because theability of the polymer backbone prevents the employment of harsherhydrolysis techniques.

[0063] The bromine- and iodine-substituted dihydroxy compounds alsoinclude the aliphatic-aromatic dihydroxy compounds having the structureof Formula III in which R₀, R₅, R₆, R₁₅, X₂, Y2 and Z are the same asdescribed above with respect to Formula III. Among the preferredaliphatic-aromatic dihydroxy compounds are compounds of Formula m inwhich R₁₅ is (—CH₂—)_(m), wherein m is 0, Y2 is 1 and R₅ and R₆ arepreferably independently selected from hydrogen and methyl. Z preferablyhas a structure according to Formula IV in which L is hydrogen or anethyl, butyl, hexyl, octyl or benzyl group. L is more preferablyhydrogen or an ethyl or benzyl group. When R₅ and R₆ are hydrogen, andR₁₅ (—CH₂—)_(m), wherein m=0, the dihydroxy compound is derived fromglycolic acid. When R₁₅ is the same, R₅ is hydrogen and R₆ is methyl,the dihydroxy compound is derived from lactic acid. Dihydroxy compoundsderived from glycolic of lactic acid are particularly preferred.

[0064] Aliphatic-aromatic dihydroxy compounds that are not bromine- oriodine-substituted have the structure of Formula IIIc:

[0065] wherein R₁₆, R₁₇, R₁₈, R₁₉, and Z are the same as described abovewith respect to Formula IIIb. Preferably, R₁₈ (—CH₂—)_(d), in which d is0 and R₁₆ and R₁₇ independently selected from hydrogen and methyl. Mostpreferably, one of R₁₆ and R₁₇ is hydrogen, while the other is methyl.The preferred species of Z are the same as described above with respectto Formula III.

[0066] The bromine- and iodine-substituted dihydroxy monomers of thepresent invention are prepared by well-known iodination and brominationtechniques that can be readily employed by those of ordinary skill inthe art without undue experimentation to prepare the monomer compoundsdepicted in Formulae I and III. The substituted phenols from which thedihydroxy monomers of the present invention are prepared undergoortho-directed halogenation. For this reason, meta-iodinated andbrominated dihydroxy monomers are not readily prepared, and triiodo- andtribromophenyl compounds have not been described. Such compounds areintended to be included within the scope of the present invention,should a convenient method for their synthesis be discovered.

[0067] Iodine- and bromine-substituted diphenol monomers may beprepared, for example, by coupling together two phenol compounds inwhich either or both of the phenol rings are iodine- orbromine-substituted. More specifically, desaminotyrosyl-tyrosine estersmay be prepared by the methods described in the above-incorporated U.S.Pat. Nos. 5,587,507 and 5,670,602 using desaminotyrosine and tyrosinealkyl esters in which either or both compounds are bromine- oriodine-substituted. In a particularly preferred embodiment,desaminotyrosine is mono-iodinated at the ortho position on the phenolicring and subsequently coupled with a tyrosine alkyl ester to obtain aniodine-substituted diphenol monomer.

[0068] Iodine- and bromine-substituted aliphatic-aromatic dihydroxymonomers in accordance with the present invention are prepared bycoupling an α-, β- or γ-hydroxy acid with a phenolic compound in whicheither or both of the hydroxy acid and the diphenol are iodine- orbromine-substituted. For example, a tyrosine alkyl ester ismono-iodinated at the ortho position on the phenolic ring andsubsequently coupled with an α-, β- or γ-hydroxy acid according to themethod described in the above-incorporated International Publication98/36013 to obtain an iodine-substituted aliphatic-aromatic dihydroxymonomer.

[0069] Polycarbonates, polyarylates, poly(alkylene oxide) blockcopolymers thereof having pendent free carboxylic acid groups alsocannot be polymerized from an aliphatic-aromatic dihydroxy monomerhaving a pendent free carboxylic acid group because of cross-reactionwith the co-monomer. Methods for preparing the aliphatic-aromaticdihydroxy monomers of Formulae III and IIIc in which L of Z is nothydrogen are disclosed in commonly owned International Publication No.98/36013, the disclosure of which is hereby incorporated by reference. Lof Z is preferably an ethyl, butyl, hexyl, octyl or benzyl group.Polycarbonates, polyarylates and the poly(alkylene oxide) blockcopolymers thereof having pendent free carboxylic acid groups can alsobe prepared by the palladium-catalyzed hydrogenolysis of thecorresponding polymers with benzyl esters prepared as described in theearlier-referenced U.S. patent application Ser. No. 09/056,050. Thecatalytic hydrogenolysis may be performed as described in thisProvisional Patent Application, as well.

[0070] Polyarylates and polycarbonates, alone, or as segments within apoly(alkylene oxide) block copolymer, may be homopolymers with eachdihydroxy monomeric subunit having an iodine or a bromine atom. Thepolymers of the present invention also include copolymers of the samepolymer units with dihydroxy monomers that are iodine- and bromine-free.One can vary within the polymers the molar ratios of the monomericsubunits having bromine- and iodine atoms and the monomeric subunitsthat are bromine- and iodine-free.

[0071] Polymers in accordance with the present invention thus includehomopolymers of a repeating unit having at least one iodine or bromineatom. Such homopolymers have the structure of Formulae VIII and VIIIa inwhich f and g are both zero.

[0072] Polymers in accordance with the present invention thus alsoinclude copolymers having monomeric repeating units that are bromine-and iodine-free. Such copolymers have the structure of Formulae VIII orVIIIa in which f is zero and g is a number greater than zero but lessthan one. In copolymers in accordance with the present invention, g ispreferably between about 0.25 and about 0.75.

[0073] In the preferred homopolymers and copolymers of Formula VIII, R₉has the structure of Formula II and R₁₂ has the structure of Formula V.The preferred species thereof are the same as described above withrespect to Formula II and Formula V.

[0074] When A of Formulae VIII and VIIIa is:

[0075] the polymers of the present invention are polycarbonates. When fis zero, the iodine- and bromine-substituted polycarbonate homopolymersand copolymers of the present invention may be prepared by the methoddescribed by U.S. Pat. No. 5,099,060 and by U.S. patent application Ser.No. 08/884,108, filed Jun. 27, 1997, the disclosures of both of whichare also incorporated herein by reference. The described method isessentially the conventional method for polymerizing dihydroxy monomersinto polycarbonates. Suitable processes, associated catalysts andsolvents are known in the art and are taught in Schnell, Chemistry andPhysics of Polycarbonates, (Interscience, New York 1964), the teachingsof which are incorporated herein by reference.

[0076] The polycarbonate homopolymers and copolymers in accordance withthe present invention in which f=0 have weight-average molecular weightsranging between about 20,000 to about 400,000 daltons, and preferablyabout 100,000 daltons, measured by gel permeation chromatography (GPC)relative to polystyrene standards without further correction.

[0077] When A of Formulae VIII and VIIIa is:

[0078] the polymers of the present invention are polyarylates. Theiodine- and bromine-substituted polyarylate homopolymers and copolymersof the present invention may be prepared by the method described by U.S.Pat. No. 5,216,115, in which dihydroxy monomers are reacted withaliphatic or aromatic dicarboxylic acids in a carbodiimide mediateddirect polyesterification using 4-(dimethylamino)pyridinium-p-toluenesulfonate (DPTS) as a catalyst to form aliphatic or aromaticpolyarylates. The disclosure of this patent is also incorporated hereinby reference. It should be noted that R₈ should not be substituted withfunctional groups that would cross-react.

[0079] Dicarboxylic acids from which the polyarylates materials of thepresent invention may be polymerized have the structure of Formula X:

[0080] in which, for the aliphatic polyarylates, R₈ is selected fromsaturated and unsaturated, substituted and unsubstituted alkyl groupscontaining up to 18 carbon atoms, and preferably from 4 to 12 carbonatoms. For aromatic polyarylates, R₈ is selected from aryl and alkylarylgroups containing up to 18 carbon atoms, but preferably from 8 to 14carbon atoms. Again, R₈ should not be substituted with functional groupsthat would cross-react.

[0081] R₈ is even more preferably selected so that the dicarboxylicacids from which the polyarylate starting materials are polymerized areeither important naturally-occurring metabolites or highly biocompatiblecompounds. Preferred aliphatic dicarboxylic acids therefore include theintermediate dicarboxylic acids of the cellular respiration pathwayknown as the Krebs Cycle. These dicarboxylic acids includealpha-ketoglutaric acid, succinic acid, fumaric acid, maleic acid andoxalacetic acid. Other preferred biocompatible aliphatic dicarboxylicacids include sebacic acid, adipic acid, oxalic acid, malonic acid,glutaric acid, pimelic acid, suberic acid and azelaic acid. Among thepreferred aromatic dicarboxylic acids are terephthalic acid, isophthalicacid and bis(p-carboxyphenoxy) alkanes such as bis(p-carboxyphenoxy)propane. Stated another way, R₈ is more preferably a moiety selectedfrom —CH₂—C(═O)—, —CH₂—CH₂—C(═O)—, —CH═CH— and (—CH₂—), wherein z is aninteger between two and eight, inclusive.

[0082] Iodine- and bromine-substituted polyarylate homopolymers andcopolymers in accordance with the present invention have weight averagemolecular weights between about 20,000 and about 400,000 daltons, andpreferably about 100,000 daltons, measured by GPC relative topolystyrene standards without further correction.

[0083] Iodine- and bromine-substituted polycarbonates and polyarylatesin accordance with the present invention also include random blockcopolymers with a poly(alkylene oxide) with the structure of FormulaeVIII or VIIIa, wherein f is greater than zero but less than one. Thevariable species, and the preferred embodiments thereof, are the same asdescribed above with respect to formulae VIII and VIIIa, except that fis no longer zero and the value for g is less than one, and g may or maynot be greater than zero.

[0084] The molar fraction of alkylene oxide in the block copolymer, f,ranges between about 0.01 and about 0.99. For preferred blockcopolymers, R₇ is ethylene, k is between about 20 and about 200, and themolar fraction of alkylene oxide in the block copolymer, f, preferablyranges between about 0.05 and about 0.75. R₇ may also represent two ormore different alkylene groups within a polymer.

[0085] The block copolymers of the present invention may be prepared bythe method described by U.S. Pat. No. 5,658,995, the disclosure of whichis also incorporated herein by reference. The block copolymers haveweight-average molecular weights between about 20,000 and about 400,000daltons, and preferably about 100,000 daltons. The number-averagemolecular weights of the block copolymers are preferably above about50,000 daltons. Molecular weight determinations are measured by GPCrelative to PEG standards without further correction.

[0086] For homopolymers and copolymers in accordance with the presentinvention having pendent carboxylic acid amide or ester groups, theamide or ester group can be an amide or ester derivative of abiologically or pharmaceutically active compound covalently thereto. Thecovalent bond is by means of an amide bond when in the underivatizedbiologically or pharmaceutically active compound a primary or secondaryamine is present at the position of the amide bond in the derivative.The covalent bond is by means of an ester bond when in the underivatizedbiologically or pharmaceutically active compound a primary hydroxyl ispresent at the position of the ester bond in the derivative. Thebiologically or pharmaceutically active compounds may also bederivatized at a ketone, aldehyde or carboxylic acid group with alinkage moiety such as the linkage moiety R₃ of Formula IIIa, which iscovalently bonded to the copolymer or diphenol by means of an amide orester bond

[0087] Detailed chemical procedures for the attachment of various drugsand ligands to polymer bound free carboxylic acid groups have beendescribed in the literature. See, for example, U.S. Pat. Nos. 5,219,564and 5,660,822; Nathan et al, Bio. Cong. Chem., 4, 54-62 (1993) andNathan, Macromolecules, 25, 44-76 (1992). The disclosures of bothpatents in both journal articles are incorporated herein by reference.These publications disclose procedures by which polymers having pendentfree carboxylic acid group are reacted with moieties having reactivefunctional groups, or that are derivatized to contain active functionalgroups to form a polymer conjugate.

[0088] The order of reaction can also be reversed. The moiety may firstbe attached to a monomer having a pendent free carboxylic acid group,which is then polymerized to form a polymer in which 100% of the pendentfree carboxylic acid groups have moieties attached thereto.

[0089] When a polymer having pendent free carboxylic acid groups isfirst polymerized and then reacted with a biologically orpharmaceutically active compound or derivative thereof to form a polymerconjugate not all of the pendent free carboxylic acid groups will have abiologically or pharmaceutically active compound covalently attachedthereto. Typically, a conjugate is formed in which biologically orpharmaceutically active compounds attach to at least about 25% of thependent free carboxylic acid groups.

[0090] Examples of biologically or pharmaceutically active compoundssuitable for use with the present invention include acyclovir,cephradine, malphalen, procaine, ephedrine, adriamycin, daunomycin,plumbagin, atropine, quinine, digoxin, quinidine, biologically activepeptides, chlorin e₆, cephradine, cephalothin, proline and prolineanalogs such as cis-hydroxy-L-proline, melphalan, penicillin V, aspirin,nicotinic acid, chemodeoxycholic acid, chlorambucil, and the like.Biologically active compounds, for purposes of the present invention areadditionally defined as including cell attachment mediators,biologically active ligand and the like. The compounds are covalentlybonded to the polycarbonate or polyarylate copolymer by methods wellunderstood by those of ordinary skill in the art. Drug deliverycompounds may also be formed by physically blending the biologically orpharmaceutically active compound to be delivered with the polymers ofthe present invention. Either way, the polymers of the present inventionprovide a means by which drug delivery may be monitored using x-rayimaging without having to employ a filler material to provide x-raycontrast.

[0091] For purposes of the present invention, the alkyl ester and amidegroups within Z are also defined as including crosslinking moieties,such as molecules with double bonds (e.g., acrylic acid derivatives),which can be attached to the pendent carboxylic acid groups forcrosslinking to increase the strength of the polymers.

[0092] As noted above, the polymers of the present invention are iodineor bromine substituted at selected repeating subunits. For the purposesof the present invention, homopolymers (Formula VIII or VIIIa, x=0) aredefined as containing an iodine or bromine at each subunit. Thesehomopolymers can be polycarbonates or polyarylates which may containpolyalkylene oxide blocks. The homopolymers are best described as new,radio-opaque polymers that may have a number of pharmacological andbiological activities. Likewise, for the purposes of the presentinvention, copolymers (Formula VIII or VIIIa, 0 <×<1) are defined ascontaining iodine or bromine at some of the diphenolic subunits. Thesecopolymers can be polycarbonates or polyarylates, which also may containpolyalkylene oxide blocks.

[0093] The invention described herein also includes variouspharmaceutical dosage forms containing the polymers of the presentinvention. The pharmaceutical dosage forms include those recognizedconventionally, e.g. tablets, capsules, oral liquids and solutions,drops, parenteral solutions and suspensions, emulsions, oral powders,inhalable solutions or powders, aerosols, topical solutions,suspensions, emulsions, creams, lotions, ointments, transdermal liquidsand the like.

[0094] The pharmaceutical dosage forms may include one or morepharmaceutically acceptable carriers. Such materials are non-toxic tothe recipients at the dosages and concentrations employed, and includediluents, solubilizers, lubricants, suspending agents, encapsulatingmaterials, penetration enhancers, solvents, emollients, thickeners,dispersants, buffers such as phosphate, citrate, acetate and otherorganic acid salts, anti-oxidants such as ascorbic acid, preservatives,low molecular weight (less than about 10 residues) peptides such aspolyarginine, proteins such as serum albumin, gelatin, orimmunoglobulins, other hydrophilic polymers such aspoly(vinylpyrrolidinone), amino acids such as glycine, glutamic acid,aspartic acid, or arginine, monosaccharides, disaccharides, and othercarbohydrates, including cellulose or its derivatives, glucose, mannose,or dextrines, chelating agents such as EDTA, sugar alcohols such asmannitol or sorbitol, counterions such as sodium and/or nonionicsurfactants such as tween, pluronics or PEG.

[0095] The drug-polymer compositions of the present invention,regardless of whether they are in the form of polymer-drug conjugates orphysical admixtures of polymer and drug, are suitable for applicationswhere localized drug delivery is desired, as well as in situations wherea systemic delivery is desired. The polymer-drug conjugates and physicaladmixtures may be implanted in the body of a patient in need thereof, byprocedures that are essentially conventional and well-known to those ofordinary skill in the art.

[0096] Hydrolytically stable conjugates are utilized when the biologicalor pharmaceutical compound is active in conjugated form. Hydrolyzableconjugates are utilized when the biological or pharmaceutical compoundis inactive in conjugated form. The properties of the poly(alkyleneoxide) dominate the polymer and conjugate thereof

[0097] Conjugates of the polymers of the present invention with prolineand proline analogs such as cis-hydroxy-L-proline may be used in thetreatment methods disclosed in U.S. Pat. No. 5,660,822. The disclosureof this patent is incorporated herein by reference.

[0098] Physical admixtures of drug and polymer are prepared usingconventional techniques well-known to those of ordinary skill in theart. For this drug delivery embodiment, it is not essential that thepolymer have pendent free carboxylic acid groups.

[0099] The drug components to be incorporated in the polymer-drugconjugates and physical admixtures of this invention may be provided ina physiologically acceptable carrier, excipient stabilizer, etc., andmay be provided in sustained release or timed release formulationssupplemental to the polymeric formulation prepared in this invention.The carriers and diluents listed above for aqueous dispersions are alsosuitable for use with the polymer-drug conjugates and physicaladmixtures.

[0100] Subjects in need of treatment, typically mammalian, using thepolymer-drug combinations of this invention, can be administered drugdosages that will provide optimal efficacy. The dose and method ofadministration will vary from subject to subject and be dependent uponsuch factors as the type of mammal being treated, its sex, weight, diet,concurrent medication, overall clinical condition, the particularcompounds employed, the specific use for which these compounds areemployed, and other factors which those skilled in the medical arts willrecognize. The polymer-drug combinations of this invention may beprepared for storage under conditions suitable for the preservation ofdrug activity as well as maintaining the integrity of the polymers, andare typically suitable for storage at ambient or refrigeratedtemperatures.

[0101] Aerosol preparations are typically suitable for nasal or oralinhalation, and may be in powder or solution form, in combination with acompressed gas, typically compressed air. Additionally, aerosols may beused topically. In general, topical preparations may be formulated toenable one to apply the appropriate dosage to the affected area oncedaily, and up to three to four times daily, as appropriate.

[0102] Depending upon the particular compound selected, transdermaldelivery may be an option, providing a relatively steady delivery of thedrug, which is preferred in some circumstances. Transdermal deliverytypically involves the use of a compound in solution, with an alcoholicvehicle, optionally a penetration enhancer, such as a surfactant, andother optional ingredients. Matrix and reservoir type transdermaldelivery systems are examples of suitable transdermal systems.Transdermal delivery differs from conventional topical treatment in thatthe dosage form delivers a systemic dose of the drug to the patient.

[0103] The polymer-drug formulations of this invention may also beadministered in the form of liposome delivery systems, such as smallunilamellar vesicles, 5 large unilamellar vesicles and multilamellarvesicles. Liposomes may be used in any of the appropriate routes ofadministration described herein. For example, liposomes may beformulated that can be administered orally, parenterally, transdermally,or via inhalation. Drug toxicity could thus be reduced by selective drugdelivery to the affected site. For example, if the drug is liposomeencapsulated, and is injected intravenously, the liposomes used aretaken up by vascular cells and locally high concentrations of the drugcould be released over time within the blood vessel wall, resulting inimproved drug action. The liposome encapsulated drugs are preferablyadministered parenterally, and particularly, by intravenous injection.

[0104] Liposomes may be targeted to a particular site for drug release.This would obviate excessive dosages that are often necessary to providea therapeutically useful dosage of a drug at the site of activity, andconsequently, the toxicity and side effects associated with higherdosages.

[0105] The drugs incorporated into the polymers of this invention maydesirably further incorporate agents to facilitate their deliverysystemically to the desired drug target, as long as the delivery agentmeets the same eligibility criteria as the drugs described above. Theactive drugs to be delivered may in this fashion be incorporated withantibodies, antibody fragments, growth factors, hormones, or othertargeting moieties, to which the drug molecules are coupled. Thepolymer-drug combinations of this invention may be formed into shapedparticles, such as valves, stents, tubing, prostheses, and the like.

[0106] Therapeutically effective dosages may be determined by either invitro or in vivo methods. For each particular compound of the presentinvention, individual determinations may be made to determine theoptimal dosage required. The range of therapeutically effective dosageswill naturally be influenced by the route of administration, thetherapeutic objectives, and the condition of the patient. For thevarious suitable routes of administration, the absorption efficiencymust be individually determined for each drug by methods well known inpharmacology. Accordingly, it may be necessary for the therapist totiter the dosage and modify the route of administration as required toobtain the optimal therapeutic effect. The determination of effectivedosage levels, that is, the dosage levels necessary to achieve thedesired result, will be within the ambit of one skilled in the art.Typically, applications of compound are commenced at lower dosagelevels, with dosage levels being increased until the desired effect isachieved. The release rate of the drug from the formulations of thisinvention are also varied within the routine skill in the art todetermine an advantageous profile, depending on the therapeuticconditions to be treated.

[0107] A typical dosage might range from about 0.001 mg/k/g to about1,000 mg/k/g, preferably from about 0.01 mg/k/g to about 100 mg/k/g, andmore preferably from about 0.10 mg/k/g to about 20 mg/k/g.Advantageously, the compounds of this invention may be administeredseveral times daily, and other dosage regimens may also be useful.

[0108] In practicing the methods of this invention, the polymer-drugcombinations may be used alone or in combination with other therapeuticor diagnostic agents. The compounds of this invention can be utilized invivo, ordinarily in mammals such as primates such as humans, sheep,horses, cattle, pigs, dogs, cats, rats and mice, or in vitro.

[0109] The polymers of the present invention also find application inareas where both solid materials and solvent-soluble materials arecommonly employed. Such applications include polymeric scaffolds intissue engineering applications and medical implant applications,including the use of the polymers of the present invention to formshaped articles such as vascular grafts and stents, bone plates,sutures, implantable sensors, scaffolds for tissue regeneration, andother therapeutic agent particles that decompose harmlessly within aknown period of time. Shaped particles can be formed by conventionaltechniques such as extrusion, compression molding, injection molding,solvent casting, spin casting, and the like.

[0110] The polymers of the present invention are soluble in both waterand organic media. Accordingly, they can be processed by solvent castingtechniques and are good film formers. The polymers of the presentinvention having pendent free carboxylic acid groups can also be used toinfluence the interactions with cells, as disclosed in theabove-referenced International Publication No. 98/36013.

[0111] The incorporation of polyalkylene oxide blocks decreases theadhesiveness of the polymeric surfaces. Polymers for which f is greaterthan 5 mole percent according to Formulae VIII or VIIIa are resistant tocell attachment and may be useful as non-thrombogenic coatings onsurfaces in contact with blood. These polymers also resist bacterialadhesion. The polymers thus can be formed as a coating on the surface ofmedical devices by conventional dipping or spray coating techniques toprevent the formation of blood clots or the adhesion of bacteria on thesurface of the device.

[0112] The film forming properties of polymers with poly(alkylene oxide)can be advantageously combined with the resistance to cell attachment toprovide films for use as barriers for the prevention of surgicaladhesions. A coating of the polymer of the present invention may also beapplied to injured tissue to provide a surgical adhesion barrier.

[0113] The polymers of the present invention can find application inareas where both structural solid materials and water-soluble materialsare commonly employed. Such applications include polymeric scaffolds intissue engineering applications and medical implant applications,including the use of the polycarbonates and polyarylates of the presentinvention to form shaped articles such as vascular grafts and stents,bone plates, sutures, implantable sensors, barriers for surgicaladhesion prevention, implantable drug delivery devices, scaffolds fortissue regeneration, and other therapeutic agent articles that decomposeharmlessly within a known period of time.

INDUSTRIAL APPLICABILITY

[0114] Shaped articles may be prepared from the polymers of the presentinvention for medical implant and drug delivery applications. Thearticles are radio-opaque and may be monitored using x-ray imagingwithout having to employ a filler material to provide x-ray contrast.

[0115] The following non-limiting examples set forth hereinbelowillustrate certain aspects of the invention. All parts and percentagesare by mole percent unless otherwise noted and all temperatures are indegrees Celsius. All solvents were HPLC grade. All other reagents wereof analytical grade and were used as received.

[0116] The following Examples illustrate the preparation of3-(3-iodo4-hydroxyphenyl)propanoic acid-tyrosine ethyl ester (DiTE), andits incorporation into a variety of polymer structures. Since an iodineis present is the structure of DiTE, the materials illustrated in thefollowing Examples are radio-paque.

EXAMPLE 1 Synthesis of DiTE

[0117] DiTE (3-(3-iodo-4-hydroxyphenyl)propanoic acid-tyrosine ethylester) is a bisphenol carrying one iodine atom at position 3 of one ofthe two phenolic rings. This bifunctional molecule can be polymerized asillustrated in the subsequent Examples. This Example describes themethod used to introduce the iodine atom in the aromatic ring(4-hydroxyphenyl)propionic acid, and the coupling of this iodinatedderivative with tyrosine ethyl ester in order to obtain DiTE.

[0118] Preparation of solution (a): to a 250 mL Erlenmeyer flask wereadded 100 mL of distilled water, 24 g of potassium iodide, and 25 g ofiodine. The mixture was stirred overnight until all solids dissolved.

[0119] Preparation of solution (b): 16.6 g (0.1 mole) of DAT were placedin a 3-necked Morton-type round bottom flask, equipped with an overheadmixer and a 125 mL addition funnel. 140 mL of 40% trimethylaminesolution in water were added, and the mixture was stirred until a clearsolution was obtained.

[0120] Solution (a) was placed in the addition funnel, and addeddropwise to solution while vigorously stirring. Addition of each drop ofsolution (a) imparted a brown color to the reaction mixture. The rate ofaddition was such that all the color disappeared before the next dropwas added. Stirring was continued for one hour after the last addition,the 50 mL of sodium thiosulfate 0.1 M were added to the reaction vessel.The same solution was also used to wash the addition funnel. 37% HCl wasadded dropwise with vigorous mixing until the solution was slightlyacidic to litmus, and a solid formed. The mixture was concentrated tohalf its volume by rotary evaporation, and then it was extracted withether. The organic phase was dried over magnesium sulfate, anddecolorized using animal charcoal. The slurry was then filtered througha small layer of silica gel, and evaporated to dryness. The white solidwas recrystallized twice in toluene, recovered by filtration, driedunder a stream of nitrogen, and then under high vacuum.

[0121] Characterization: DSC analysis showed a melting point range of109-111° C. ¹H—NMR (DMSO) of the product showed the following peaks(ppm): 2.5 (t, 2H), 2.7 (t, 2H), 6.8 (d, 2H), 7.06 (d, 2H), 10.08 (s,1H), 12.05 (s, 1H). Reverse-phase HPLC showed 3.8% DAT (the startingmaterial), and 1.4% of diiodinated product.

Step 2 Preparation of 3-(3-iodo-4-hydroxyphenyl)propionic acid-tyrosineethyl ester (DiTE)

[0122] To a 250 mL 3-necked round bottomed flask equipped with anoverhead stirrer were added 17.0 g (0.0582 moles) of DiAT, 12.25 g(0.0585 moles) or tyrosine ethyl ester, and 25 mL of NMP. The mixturewas stirred until a clear solution was obtained. The flask was cooled inan ice-water bath, the 11.84 g (0.0619 moles) of EDCI HCl were added inone portion, followed by 15 nL of NMP. The cooling bath was removedafter 2.5 hours, and the reaction was allowed to continue overnight atroom temperature. 71 mL of ethyl acetate were added, and stirring wasmaintained for 15 more minutes. The crude was then transferred into a500 mL separatory funnel, and extracted once with 75 mL of brine, thenwith two aliquots (75 and 35 mL) of 3% NaHCO3/14% NaCl, followed by 35mL aliquots of 0.4 M HCl/14% NaCl, and finally with brine. The organicphase was dried over magnesium sulfate and treated with activatedcarbon, filtered and concentrated to a thick syrup, which crystallizedinto a solid mass after a few hours. The product was triturated inmethylene chloride using mechanical stirring, then it was recovered byfiltration and dried under a nitrogen stream followed by high vacuum.

[0123] Characterization: DSC analysis showed a melting point range of110-113° C. ¹H—NMR (DMSO) showed the following peaks (ppm): 1.1 (t, 3H),2.35 (t, 2H), 2.65 (m, 2H), 2.85 (m, 2), 4.05 (q, 2H), 4.35 (m, 1H),6.65/6.75/6.95 (m, 6H), 7.5 (s, 1H), 8.25 (d, 1H), 9.25 (s, 1H), 10.05(s, 1H). Reverse-phase HPLC showed 2.2% of DTE (the non-iodinatedmonomer), and no diiodinated product.

EXAMPLE 2 Poly(DiTE carbonate) by solution polymerization

[0124] This material is the polycarbonate obtained by reacting DiTE,obtained in Example 1, and phosgene.

[0125] Polymerization of DiTE with Phosgene

[0126] A 250 mL 3-necked flask equipped with a mechanical stirrer and anaddition funnel was purged with nitrogen for 15 minutes. 7.62 g (15.8moles) of DiTE were added to the flask followed by 39 mL methylenechloride and 4.79 mL distilled pyridine. The mixture was stirred until aclear solution was obtained, then it was chilled in an ice-water bath.9.8 mL of 20% phosgene solution in toluene were placed in the additionfunnel and added to the reaction flask at a constant rate so that theentire addition was complete in 1.5 hours. The mixture was stirred forone more hour, then it was diluted with 200 mL THF, and the polymer wasprecipitated by dropping the solution in a large excess of ether througha filter funnel. The precipitated polymer was washed with ether,transferred to an evaporating dish, and dried overnight under a steam ofnitrogen. It was redissolved in THF, and precipitated again in awater/ice mixture, using a high-speed blender. The product was thendried under a stream of nitrogen, followed by high vacuum at 40° C.

[0127] Characterization: The composition of the product was confirmed byElemental Analysis: %C=50.60 (theor: 49.52%); %H=4.21 (theor: 3.96%);%N=2.65 (theor: 2.75%); %I-24.01 (theor: 24.92%). A Mw of 104K with apolydispersity of 1.8 was determined by GPC in THF vs. polystyrenestandards. DSC showed a Tg of 103.8° C. ¹H—NMR (DMSO-D₆) showed thefollowing peaks (ppm): 1.1 (t, 3H), 2.4 (broad, 2H), 2.75 (broad, 2H),3.0 (broad, 2H), 4.05 (q, 2H), 4.45 (m, 1H), 7.3 (m, 6H), 7.8 (s, 1H),8.4 (d, 1H).

EXAMPLE 3 Poly(DiTE-co-5% PEG1K carbonate) by solution polymerization

[0128] In this Example, 5 mole % of PEG1000 was copolymerized with DiTEthrough phosgenation by means of a solution polymerization techniquesimilar to that described in Example 2. The resulting material is arandom polycarbonate.

[0129] Copolymerization of DiTE and PEG1000

[0130] A 100 mL 3-necked round bottomed flask equipped with an additionfunnel and an overhead stirrer was purged with nitrogen for 30 minutes.The flask was charged with 5 g (10.33 mmoles) of DiTE, and 0.545 g (0.55imoles) of PEG1000, then 23 mL of methylene chloride and 3.3 mL ofpyridine were added, and the mixture was stirred until a colorless,clear solution resulted. The flask was cooled in an ice-water bath, and6.4 mL of 20% phosgene solution in toluene were added dropwise over aperiod of 90 minutes from the addition funnel. The mixture was dilutedwith 90 mL of THE, and stirred for one more hour. The product wasisolated by precipitation in 800 mL of ethyl ether, and dried under astream of nitrogen followed by high vacuum.

[0131] Characterization: A Mw of 75,500 with a polydispersity of 1.8 wasdetermined by GPC vs. polystyrene standards, with THF as the mobilephase. DSC showed Tg of 70° C. ¹H—NMR (CDCl₃) showed the following peaks(ppm): 1.2 (t, 3H), 2.45 (broad, 2H), 2.8 (broad, 2H), 2.03 (broad, 2H),3.65 (s, 4.5 PEG protons), 4.15 (q, 2H),4.85 (m, 1H), 6.05 (broad, 1H),7.05/7.15 (m, 6H), 7.2 (s, 1). The peaks at 7.05/7.15, and at 7.2 arediagnostic for the presence of the iodine atom on the aromatic system ofthe polymer. Broad-Band Decoupled ¹³C NMR (CDCl₃) showed all theexpected peaks, and in particular that of the aromatic carbon bearingthe iodine (90 ppm).

EXAMPLE 4 Poly(DiTE adipate) by Solution Polymerization

[0132] This material is an alternating copolymer of theiodine-containing diphenol DiTE, and adipic acid, an aliphatic diacid.The monomers are linked through an ester bond to form a polyarylatebackbone. This Example illustrates the preparation of this copolymer bymeans of a condensation reaction promoted by the coupling agentdiisopropylcarbodiimide (DIPC).

[0133] Copolymerization of DiTE and Adipic Acid

[0134] A 100 mL round bottomed flask equipped with an overhead stirrerwas purged with nitrogen for one hour, and then charged with 4.349 g(9.0 mmoles) of DiTE, 1.315 g (9.0 mmoles) of adipic acid, 1.06 ofdimethylaminopyridinium p-toluene sulfonate (2.5 mmoles), and 68 mL ofmethylene chloride. The mixture was stirred for five minutes, then 4.2mL (27 mmoles) of DIPC were added in one portion. Stirring was continuedovernight at room temperature, then the reaction crude was filtered, andthe polymer was precipitated in 600 mL of chilled isopropanol in ahigh-speed blender, and isolated by filtration. The polymer was washedin the high-speed blender with 600 mL of chilled isopropanol, and the600 mL of a water/ice mixture. The product was dried overnight under astream of nitrogen, and then was transferred to high vacuum at roomtemperature.

[0135] Characterization: A Mw of 67,100 with a polydispersity of 1.9 wasdetermined by GPC vs. polystyrene standards, with THF as the mobilephase. DSC showed a Tg of 66.5° C. ¹H—NMR (DMSO-D₆) showed the followingpeaks (ppm): 1.1 (t, 3H), 1.75 (broad, 4H), 2.4 (broad, 2H), 2.7 (broad,6H), 2.95 (broad, 2H), 4.05 (q, 2H0, 4.45 (m, 1H), 7.05/7.15 (m, 6H),7.7 (s, 1H), 8.4 (d, 1H).

EXAMPLE 6 Fabrication and Implantation of Radio-Opaque Rods

[0136] Iodine-containing, radio-opaque polymers can be blended withnonradio-opaque materials in order to fabricate implantable devices thatare x-ray detectable. This example illustrates the preparation of blendsof poly(DTE carbonate) and poly(DiTE carbonate) in three differentratios, their fabrication into rods, and their implantation into ananimal model.

[0137] Preparation of Radio-opaque Polymer Blends

[0138] Three blends with different ratios of poly(DTE carbonate) (Mw=103K) to poly(DiTE carbonate) (Mw=106 K) were prepared. The weight ratioswere 90/10, 75/25 and 50/50. In each case, the polymers wereco-dissolved in methylene chloride, and the mixture was precipitated inether.

[0139] Fabrication and Implantation of Radio-opaque Rods

[0140] Uniform rods of 10 mm length, 2 mm diameter were obtained by meltextrusion at 180° C. The rods were implanted in rabbit long bones, andsites of implantation were x-rayed in order to confirm the radio-opacityof the devices. Radio-opacity increased with increasing content ofpoly(DiTE carbonate).

[0141] The foregoing examples illustrate that radio opacity may beobtained by Br and I ring-substitution of essentially any aromaticring-containing polymer. These examples, and the foregoing descriptionof the preferred embodiment, should be taken as illustrating, ratherthan as limiting, the present invention as defined by the claims. Aswill be readily appreciated, numerous variations and combinations of thefeatures set forth above can be utilized without departing from thepresent invention as set forth in the claims. Such variations are notregarded as a departure from the spirit and scope of the invention, andall such modifications are intended to be included within the scope ofthe following claims.

What is claimed is:
 1. An implantable, radio-opaque medical device comprising a radio-opaque, iodine- or bromine-containing polymer having at least one repeating unit derived from a monomer described by the formula (I):

wherein X₁ and X₂ are independently iodine or bromine, Y1 and Y2 are independently 0, 1 or 2, and R₉ is an alkyl, aryl or alkylaryl group containing up to 18 carbon atoms optionally substituted with iodine or bromine.
 2. The implantable, radio-opaque medical device of claim 1, wherein R₉ has the structure (II):

wherein R₀ is selected from the group consisting of —CH═CH—, —CHJ₁—CHJ₂— and (—CH₂—)_(m); R₄ is selected from the group consisting of —CH═CH—, —CHJ₁—CHJ₂— and (—CH₂—)_(n), in which m and n are independently 0 to 8, inclusive, and J₁ and J₂ are independently Br or I; and Z is selected from the group consisting of hydrogen, a free carboxylic acid group and esters and amides thereof, said ester and amide being selected from the group consisting of straight and branched alkyl and alkylaryl groups containing up to 18 carbon atoms and derivatives of biologically and pharmaceutically active compounds.
 3. The implantable, radio-opaque medical device of claim 2, wherein R₄ is —CH₂— or —CHJ₁—CHJ₂— and R₀ is —CH₂— or —CH₂—CH₂—.
 4. The implantable, radio-opaque medical device of claim 2, wherein Z is a free carboxylic acid group, or an ethyl, butyl, hexyl, octyl or benzyl ester or amide thereof.
 5. The implantable, radio-opaque medical device of claim 1, wherein Y₁+Y₂ is greater than zero.
 6. The implantable, radio-opaque medical device of claim 1 wherein said medical device is formed from said polymer.
 7. The implantable, radio-opaque medical device of claim 1 wherein said medical device is coated with said polymer.
 8. The implantable, radio-opaque medical device of 1 wherein said device comprises a radio-opaque, biocompatible stent comprising said polymer.
 9. The implantable, radio-opaque medical device of claim 12 wherein said device is a radio-opaque, biocompatible stent.
 10. The implantable, radio-opaque medical device of claim 1, wherein said polymer further comprises one or more poly(alkylene oxide) blocks.
 11. An implantable, radio-opaque medical device comprising a radio-opaque polymer having at least one repeating unit derived from a monomer described by the formula (III):

wherein R₅ and R₆ are each independently selected from the group consisting of H, Br, I and straight and branched alkyl groups having up to 18 carbon atoms, R₀ is selected from the group consisting of —CH═CH—, —CHJ₁—CHJ₂— and (—CH₂—)m and R₁₅ is selected from the group consisting of —CH═CH—, (—CH₂—)_(c) and —CHJ₁—CHJ₂—, wherein J₁, J₂ and each X₂ are independently Br or I; c and m are independently between 0 and 8, inclusive; Y2 is 0, 1 or 2; and Z is selected from the group consisting of hydrogen, a free carboxylic acid group or an ester or amide thereof, said ester or amide comprising straight and branched alkyl and alkylaryl groups containing up to 18 carbon atoms and derivatives of biologically and pharmaceutically active compounds.
 12. The implantable, radio-opaque medical device of claim 11, wherein R₁₅ is —CH₂— or —CHJ₁—CHJ₂— and R₀ is —CH₂— or —CH₂—CH₂—.
 13. The implantable, radio-opaque medical device of claim 11, wherein Z is a free carboxylic acid group or an ethyl, butyl, hexyl, octyl or benzyl ester or amide thereof.
 14. The implantable, radio-opaque medical device of claim 11, wherein R₁₅ is (—CH₂—)_(c), c is 0 and R₁ and R₂ are independently hydrogen or a methyl group.
 15. The implantable, radio-opaque medical device of claim 14, wherein R₁ and R₂ are both hydrogen.
 16. The implantable, radio-opaque medical device of claim 14, wherein one of R₁ and R₂ is hydrogen and the other is a methyl group.
 17. The implantable, radio-opaque medical device of claim 11, wherein R₀ is —CH₂— and Z is a carboxylic acid ethyl ester.
 18. The implantable, radio-opaque medical device of claim 11, wherein Y₂ is 1 or
 2. 19. The implantable, radio-opaque medical device of claim 11, wherein said polymer further comprises one or more poly(alkylene oxide) blocks.
 20. The implantable, radio-opaque medical device of claim 11 wherein said medical device is formed from said polymer.
 21. The implantable, radio-opaque medical device of claim 11 wherein said medical device is coated with said polymer.
 22. The implantable, radio-opaque medical device of 11 wherein said device comprises a radio-opaque, biocompatible stent comprising said polymer.
 23. The implantable, radio-opaque medical device of claim 20 wherein said device is a radio-opaque, biocompatible stent. 